We have continued our studies of the expression of receptors for human interferons (IFNs) on normal and malignant peripheral blood lymphocytes, using radioiodinated recombinant IFN-alpha A and IFN-gamma. After activation of T lymphocytes, the number of IFN-alpha receptors was found to increase in parallel with the increases in cell size that accompany T cell activation. In contrast, the density of high affinity IFN-gamma receptors was 3-4-fold lower on activated than on resting T lymphocytes. At least part of the decrease was attributable to down-regulation of IFN-gamma receptors by endogenous IFN-gamma produced by the activated T cells. Moreover, resting T lymphocytes were found to have a single class of high affinity IFN-gamma receptors, whereas the activated cells had both high and lower affinity IFN-gamma binding sites. In order to study the molecular characteristics of the IFN-gamma receptor, we have developed assays to measure the binding of IFN-gamma to isolated plasma membranes. We have begun studies of the IFN-gamma receptor after solubilization with detergent as initial steps toward purification of the receptor and production of antibodies to the receptor. We have further examined the relationship between the level of IFN-alpha receptor expression on malignant cells and clinical responsiveness of patients with lympho-proliferative diseases. The results of these studies indicate that the absolute number of IFN receptors per cell is only one of several important parameters in the response to IFN therapy and that the responsiveness of a particular lymphoproliferative disease or a particular patient to IFN therapy cannot be predicted or explained solely by the level of IFN receptor expression. In studies to elucidate molecular mechanisms for the antiproliferative action of IFN, we have found that IFN-alpha alters the metabolism of adenosine in lympho-blastoid cells. We have also studied the antagonism in effects on cell proliferation between IFN and autocrine growth promoting agents produced by lymphoid cell lines.